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PubMed1999

An in vivo comparison of bacillus Calmette-Guérin (BCG) and cytokine-secreting BCG vaccines.

A recombinant bacillus Calmette-Guérin (BCG) vaccine has been developed, which constitutively secretes interleukin (IL)-2. Groups of deer were immunized with either normal BCG (Pasteur 1173 P2 strain) or recombinant BCG (rBCG/IL-2) and their immune responses were monitored over 3 months. Animals gained weight over this period and showed no signs of adverse reactions to either vaccine. Lymphocyte transformation responses did not differ significantly between the two groups. No antibody that was specific for BCG was detected in any animal. Intradermal skin-test responses to BCG antigens showed that the rBCG/IL-2 induced a smaller delayed-type hypersensitivity response than the normal BCG. Cytokine transcription was determined by reverse transcription-polymerase chain reaction (RT-PCR). While IL-2 and interferon-gamma (IFN-gamma) levels did not differ significantly between the two groups, the level of IL-4 was found to be lower in the group given rBCG/IL-2. This resulted in a strong interferon-gamma:IL-4 ratio, suggesting a skewing of the immune response towards a Type 1 response. The rate at which the vaccine was eliminated from the host was the same regardless of whether BCG or rBCG was used. At autopsy (3 months after vaccination) 99.99% of the organisms had been eliminated. The small number of organisms isolated from the draining lymph node of animals given rBCG/IL-2 were grown in antibiotic-containing media. They were shown to still contain the shuttle plasmid and to secrete biologically active IL-2, indicating that the plasmid was stably maintained despite the host's immune response and in the absence of antibiotic selection.

Animals↗

PubMed2004

Design of the leprosy component of the Brazilian BCG revaccination trial for assessing BCG effectiveness against leprosy in school children.

BACKGROUND: BCG vaccination confers protection against leprosy, and vaccination among household contacts has been recommended in Brazil. Nevertheless, vaccination of the entire community against leprosy is not advocated as leprosy has low incidence in most populations. Despite that, in Brazil, BCG vaccination is recommended among school children to prevent tuberculosis and this large scale vaccination may also affect the occurrence of leprosy, which led to investigations of its impact on leprosy in endemic areas of Brazil. OBJECTIVES: To estimate the effectiveness against leprosy of a dose of BCG vaccine given to school children in a population with a high coverage of neonatal BCG. Long term objectives are to compare the impact of vaccination among schoolchildren with the existing recommendation to vaccinate household contacts of leprosy. STUDY DESIGN: Cluster randomized controlled field trial with no placebo. STUDY POPULATION: Children aged 7 to 14 years attending state schools with high coverage of neonatal BCG. METHODS: 286 state schools in the city of Manaus, Brazil, were randomized to receive BCG or not. Identifying information was collected for 152,438 school children, of whom 72,980 are in intervention schools. BCG vaccination was given intradermically to children in schools allocated to vaccination. Follow-up relies on ascertainement of cases diagnosed at the health services and notified to the reference center for leprosy.

Adolescent↗

PubMed1979

Properties of interferon induced by purified protein derivative of tuberculin in mice sensitized with BCG or cell-wall skeleton of BCG.

Mice sensitized with either BCG or cell-wall skeleton of BCG (BCG-CWS) produced interferon in blood after stimulation with specific antigen, purified protein derivative of tuberculin (PPD). Both BCG-infected normal (C57BL/6) and thymic nude (BALB/c, nu/nu) mice showed enhanced activity to produce interferon by stimulation with E. coli endotoxin. However, detectable interferon was not produced in athymic nude mice sensitized with BCG or BCG-CWS by stimulation with PPD. Immune-induced interferon (I-IF) produced by BCG-CWS and PPD in mice was different in biological and physicochemical properties from virus-induced interferon. I-IF showed about 100 times more potent L-cell growth inhibitory activity than virus-induced L-cell interferon (L-IF). Both I-IF and L-IF showed macrophage-activating activity, which renders resting macrphages cytotoxic to L1210 leukemia cells. Antiviral and macrophage-activating activity of interferon preparation was not separated physicochemically in this study.

Animals↗

PubMed1985

[Antitumor activity of BCG--inhibition and enhancement of tumor growth by anti-BCG rabbit serum].

Administration of heat-killed BCG into BALB/c mice with colon 26 tumors which have common antigens to those of BCG has been shown to enhance tumor growth. The present experiments were undertaken to clarify this phenomenon. It was found that anti-BCG rabbit serum played a role in augmenting tumor growth when injected intraperitoneally into tumor-bearing mice. Interestingly, bi-phasic activity of anti-BCG rabbit serum (inhibition and enhancement of tumor growth) was observed, which was dependent on the concentration of BCG antibodies present. By contrast, immune-complex prepared with BCG antigen-antibody was not considered to be an agent for directly enhancing tumor growth. It was therefore concluded that anti-BCG rabbit serum was a specific agent for augmenting tumor growth.

Animals↗

PubMedDate not supplied

Interference of preceding BCG vaccination with BCG immunotherapy in L2C-guinea pig leukemia.

Guinea pigs of inbred strain 2 were vaccinated with BCG 1331 Copenhagen (K-Nr. 240-1) six to seven weeks before intradermal application of about 10(5) leukocytes from a highly leukemic animal in mixture with 10(7) colony forming units (CFU) of BCG. This presensitization with BCG totally abolished or strongly reduced the antitumor activity of L2C-cells adjoining BCG. Increase of bacterial mass applied from 1 X 10(7) to 2 X 10(8) CFU did not restore the antileukemic effect of BCG as observed in unvaccinated guinea pigs by a significant delay of death in a portion of animals and by the occurrence of long-term survivors. Since local reaction to BCG occurred much earlier in presensitized than in unvaccinated animals, we speculate that the destruction of tumor cells and hence the antigenic stimulus was too premature in presensitized animals to build up a BCG-mediated antitumor immunity.

Animals↗

PubMed1995

[BCG vs. BCG plus recombinant alpha-interferon 2b in superficial tumors of the bladder].

BCG intravesical instillation is a well established therapy for superficial bladder carcinoma as adjuvant and/or prophylactic treatment. However side-effects are frequent when full doses are employed and therefore low dose alternative schedules were proposed. Interferon intraluminal therapy for bladder TCC has been used with similar indication but the results did not encourage further single drug trials. A double arm random study, BCG full dose vs. BCG low dose, is presented. The results point out that the combination treatment is superior to BCG full dose therapy in terms of side effects and similar to BCG full dose as regards efficiency (5/18 vs 4/18 recurrences) after a follow-up of 24.11 +/- 8.15 for BCG and 16.72 +/- 8.7 for BCG + IFN.

Administration, Intravesical↗

PubMed1976

BCG vaccination and epidemiological situation: a decision making approach to the use of BCG.

The clinical efficacy of a well-controlled and correctly applied BCG vaccine can hardly be questioned, nor its usefulness under individual circumstances. But a problem more and more often raised now is that of the opportuneness, at the present time, to still use BCG on a mass- systematic - scale, particularly in the TB control programmes of low-prevalence countries. The article proposes an approach which, alongside with other methods already presented for assessing the epidemiological value of BCG and its public health indications, can help appreciate the advantages and disadvantages brought by vaccination in high- as well as in low-prevalence countries. The article focuses on the future, i.e. on what can, from now on, be expected from BCG in terms of epidemiological, economical and psychological benefits. Test runs were made considering three cohorts of 100,000 individuals (newborn, school enterers, school leavers), vaccinated or not vaccinated, submitted to various risks of infection (corresponding to conditions of high-, intermediate- and low-prevalence of tuberculosis) and experiencing various breakdown rates from infection to disease. Cost for BCG on the one hand, and cost for diagnosis, treatment of tuberculosis and loss of wages on the other, were also entered in the calculations; an attempt was also made to quantify in absolute terms and in relative ones the in conveniences linked to the application of BCG itself. Beyond figures and results presented as examples, what is more important is that the article furnished a method of reasoning and the possibility to feed one's own data in the model; it may help to encompass the scope and implications of a decision, and it furnishes elements of dialogue with other members of the planning team. It should be well realized that the elements provided and those which can be worked out are elements of reflexion to found a decision; the decision itself - to start, to pursue or to stop BCG on a mass scale - is of political nature (public health policy): it always implies a value judgement - from the part of the providers of the services and/or, preferably, from the part of the users, i.e. a preference which is the result of a 'weighing' between advantages and inevitable disadvantages, both involving time, place, existing system, existing beliefs and other fields of health and welfare.

Adolescent↗

PubMed2003

A recA deletion mutant of Mycobacterium bovis BCG confers protection equivalent to that of wild-type BCG but shows increased genetic stability.

The widely used vaccine against tuberculosis, BCG, shows evidence of genetic instability. It has undergone major genetic rearrangements resulting in deletion and duplication of segments of its chromosome. In order to produce a BCG strain with more favourable genetic properties, we inactivated the recA gene. Targeted deletion of the recA gene of BCG resulted in a complete loss of recombination between homologous, chromosomally-located sequences, as well as between plasmid- and chromosomally-located sequences. The deltarecA mutant BCG was as effective as the wild-type in conferring protection in mice against an intravenous challenge with virulent Mycobacterium tuberculosis, indicating that the loss of an SOS response-mediated DNA repair mechanism did not compromise the immunological properties of BCG. The availability of a genetically stable, fully immunogenic BCG is important for the future development of BCG as a live vaccine.

Animals↗

PubMed1982

Active specific immunotherapy of established micrometastases with BCG plus tumor cell vaccines: effective treatment of BCG side effects with isoniazid.

Intradermal vaccinations with Bacillus Calmette-Guérin (BCG) and viable but nontumorigenic syngeneic hepatocarcinoma cell vaccines were used successfully to treat micrometastatic disease experimentally induced in inbred guinea pigs at 100 times the minimal lethal dose. Several complications have been associated with the use of viable BCG organisms in the treatment of cancer patients and, in this animal model, intradermal administration of BCG uniformly results in severe ulceration and eschar formation at the injection sites leading to secondary microbial invasion and regional lymphadenopathy. We now report the use of isoniazid (Nydrazid) as part of an active specific immunization regimen. Incorporation of isoniazid into the immunization procedure for two weeks alleviates or reduces the side effects of BCG infection. Moreover, with proper consideration of BCG dosage, isoniazid does not impair the efficacy of the BCG plus tumor cell vaccines.

Animals↗

PubMed1991

Immunotherapy of bovine ocular squamous cell carcinoma by repeated intralesional injections of live bacillus Calmette-Guérin (BCG) or BCG cell walls.

UNLABELLED: Thirty cows of the Dutch Friesian and the Maas-Rijn-Ijssel breed with histologically confirmed ocular squamous cell carcinoma were treated by repeated intralesional injection of live bacillus Calmette-Guérin (BCG) (n = 14) or a BCG cell-wall vaccine (n = 16). Complete regression of the primary tumour was observed in 64% and 57% of the animals respectively. In the 2-year follow-up period there was no recurrence of primary tumours. This sharply contrasts with the recurrence frequency (40%-50%) after complete remission induced by a single intralesional injection with BCG, observed in an earlier study. In 1 animal a new primary tumour developed. At necropsy metastases were present in 33% of the treated animals: in 3 of 17 animals that showed complete regression of the primary tumour and in 7 of 13 animals with partial regression or progressive disease. This did not differ significantly from results obtained after a single treatment (27%). Delayed-type hypersensitivity to M. bovis purified protein derivative (PPD) was more persistent in animals showing regression of the primary tumour than in non-responding animals. Of the animals with a positive PPD response 6 months after treatment, 79% showed tumour regression. Regression was observed in only 28% of the animals not responding to PPD after the same period of time. IN CONCLUSION: (a) recurrence of the primary tumour was not observed after repeated BCG treatment; (b) the frequency of metastases was not decreased compared to results obtained with a single treatment; (c) regression was correlated with a positive delayed-type hypersensitivity reaction to PPD (P less than 0.05) 6 months after treatment; (d) no significant differences were observed when the clinical results of treatment with live BCG and the BCG cell wall vaccine were compared.

Animals↗

PubMed1994

Six years' experience with the discontinuation of BCG vaccination. 4. Protective effect of BCG vaccination against the Mycobacterium avium intracellulare complex.

SETTING: In 1986, mass BCG vaccination of newborns was discontinued in an extensive territorial sample of neonates in the Czech Republic (30,000 infants annually). The non-vaccinated children have since been tuberculin tested at two-year intervals; those with continual or repeated intensive contact with animals in households or on farms were also tested with Mycobacterium avium intracellulare complex sensitin in addition to tuberculin. OBJECTIVE: Within the frame work of the surveillance programme the incidence of infection and disease caused by M. avium intracellulare complex (M. avium complex) was evaluated and the protective effect of BCG vaccination analysed. DESIGN: In 1986-93, out of 190,874 non-vaccinated children, 36 were found to be infected by M. avium complex; 27 of them developed disease, i.e. mycobacteriosis other than tuberculosis (MOTT). RESULTS: The annual risk of infection with M. avium complex was 4.8/100,000 children per year, of whom 3.6/100,000 developed mycobacteriosis. 24 patients suffered from swelling of cervical lymph nodes, 2 of mediastinal lymph nodes and one child had the disease localized both in cervical and mediastinal lymph nodes. The disease was verified bacteriologically in 9 children. Most of the diseased children had impaired immunity; a marked skin reactivity of M. avium complex sensitin was present in all infected children. Animal sources infected by M. avium complex were detected in 5 cases. Another 14 children also had close contact with animals but without proven M. avium complex infection. CONCLUSION: In non-BCG vaccinated children the incidence of lymphadenitis caused by M. avium complex was considerably higher than in vaccinated children. BCG cells possess antigenic determinants which confer protective immunity probably both against M. tuberculosis and against M. avium complex infections. It may thus be assumed that BCG vaccination protects both against pathogenic tubercle bacilli and M. avium complex. This should be taken into consideration before recommending discontinuation of mass BCG vaccination of newborns in areas with a high prevalence of M. avium complex infection.

Age Distribution↗

PubMed2002

Design of the Brazilian BCG-REVAC trial against tuberculosis: a large, simple randomized community trial to evaluate the impact on tuberculosis of BCG revaccination at school age.

This paper describes the design and baseline results of a large and simple randomized controlled trial of the protection against tuberculosis of a dose of Bacillus Calmette Guerin (BCG) vaccination given to school children in a population with a high coverage of neonatal BCG (The Brazilian BCG-REVAC trial). The study started in 1996 and is a pair-matched and stratified-cluster randomized controlled trial with no placebo. The study population consists of children aged 7-14 years enrolled in 763 state schools from the cities of Salvador and Manaus, Brazil. Schools were the unit of randomization. Identifying information was collected for 354,708 school children. The final study population, after exclusions on the basis of age, BCG scar readings and absence from school on the day of the study visit, consists of 242,401 children, of whom 125,403 are in intervention schools. Follow-up relies on ascertainment of cases diagnosed at the health services and notified to the tuberculosis control program surveillance system. Blindness is guaranteed during linkage and validation of cases. Analysis is planned for the next 12 months, where efficacy will be estimated by calculating incidence of tuberculosis in the vaccine and control groups, taking into consideration the cluster design. The intervention studied, a second BCG vaccination, is widely used, although the World Health Organization does not recommend it on the basis of absence of evidence of protection or lack of protection. The results of the trial will make it possible for BCG revaccination practice to be informed by evidence. This is an example of a large simple and relatively inexpensive effectiveness trial, resulting from good collaboration between academia and health and education services enabling developing countries to define policies that are relevant for their reality.

Adolescent↗

PubMedDate not supplied

Viability, heat stability and immunogenicity of four BCG vaccines prepared from four different BCG strains.

Four BCG strains, French 1173-P2, Danish 1331, Japanese 172 and Glaxo-1077, among those most widely used throughout the world for tuberculosis vaccination, were prepared according to the respective conditions in each BCG-production unit. These 16 vaccine preparations were distributed and compared using standardized in vitro and in vivo conditions, based on optical density and bacillary mass/ml. The results presented in this report concern only the 4 freeze-dried BCG strains prepared by the Institut Pasteur BCG unit. It is shown that these 4 preparations differ in their in vitro characteristics such as growth, morphology, heat stability and viability, tested by colony-forming units and the ATP content. In addition, statistically significant differences were observed in biological control tests performed in guinea-pigs and mice when they were immunized with the same concentrations of 4 reconstituted vaccines. For instance, in tests measuring hallmarks of cell-mediated immunity--such as local granuloma formation, spleen index, delayed-type hypersensitivity to tuberculin, and non-specific immunopotentiation to unrelated antigen--a ranking order of relative immunopotency of the four strains was made, giving the following classification in decreasing order: French 1173-P2, Danish 1331, Japanese 172 and Glaxo-1077. Specific acquired resistance after BCG vaccination in mice was obtained with all four vaccines. However, higher protection was observed in mice vaccinated with Glaxo-1077 and French 1173-P2 strains. No obvious correlation existed between the intensity of cellular post-vaccination resistance and the above CMI tests, except those concerning the three-week index of BCG infection measured in the spleen, which correlated with the protection test.

Adenosine Triphosphate↗

PubMed1999

Cytolytic T-cell responses to human dendritic cells and macrophages infected with Mycobacterium bovis BCG and recombinant BCG secreting listeriolysin.

Cytolytic T-cell responses from 63 normal blood donors were monitored in a Mycobacterium bovis BCG infection system in vitro. We wanted to know whether cultured dendritic cells were capable of potentiating the cytolytic T-cell responses to M. bovis BCG. Infected cultured dendritic cells were up to ten times more effective antigen-presenting cells than macrophages in proliferative assays, while cytolytic T-cell induction did not differ significantly between dendritic cells and macrophages. Separated CD4+ and CD8+ T-cell subsets contributed equally to lysis of infected targets. Experiments comparing wild-type M. bovis BCG strain with two new recombinant M. bovis BCG strains secreting listeriolysin revealed statistically significant higher maximal lysis values for recombinant M. bovis BCG. We conclude from our in vitro infection system with mycobacteria that dendritic cells are superior to macrophages in proliferative assays but equal to macrophages in their ability to induce cytolytic T-cell responses. Moreover, our data suggest that recombinant M. bovis BCG vaccine strains secreting listeriolysin improve cytolytic T-cell responses.

Antibodies, Monoclonal↗

PubMed1996

Influence of the mouse Bcg, Tbc-1 and xid genes on resistance and immune responses to tuberculosis infection and efficacy of bacille Calmette-Guérin (BCG) vaccination.

We have studied the role of three mouse distinct non-H-2 genes (Bcg, Tbc-1, xid) in several phenomena of antituberculosis immunity and resistance. On the basis of median survival time (MST) of mice following infection with virulent Mycobacterium tuberculosis H37Rv, Bcg gene did not control resistance to the lethal dose of H37Rv infection in non-vaccinated and Myco. bovis (BCG)-vaccinated mice. However, Bcgr allele, in comparison with Bcgs allele, determined more effective suppression of an early multiplication in spleens of H37Rv mycobacteria after a low dose (5x10(4) colony-forming units (CFU)) injection. CBA/N mice, which are not protected efficiently against tuberculous challenge by BCG vaccination, were characterized by a decreased in vitro proliferation of immune lymph node cells, both spontaneous and stimulated with mycobacterial antigens. The decreased proliferation was due to immunosuppression caused by interactions between responding T cells and CBA/N antigen-presenting cells (APC). We have confirmed that the defective response to BCG-vaccination in CBA/N mice is linked with the X-chromosome and thus is presumably determined by the xid gene itself. I/St mice (Tbc-1s), supersusceptible to H37Rv infection, were not able to restrict the growth of H37Rv mycobacteria in spleens, even following infection with a low dose (5x10(4)), but restricted the growth of Myco.bovis BCG more effectively than Bcgs mice.

Animals↗

PubMed1995

Relationship between bacille Calmette-Guérin (BCG) strains and the efficacy of BCG vaccine in the prevention of tuberculosis.

Bacille Calmette-Guérin (BCG) vaccination for the prevention of tuberculosis has been used in humans since 1921. Furthermore, for > 60 years it has been possible to separate BCG strains (defined here as a BCG vaccine maintained in a particular laboratory and used in a particular trial or set of trials) on the basis of in vitro and in vivo tests. Investigators have concluded that differences in the BCG strains used in efficacy trials on humans may be responsible for the wide range in levels of protection from tuberculosis reported in those trials. We review the development of the separate strains used in the trials included in a recent meta-analysis and examine data for and against the protective efficacy of different BCG strains. The difficulties in correlating results of in vitro and in vivo tests with protective efficacy in humans are discussed. The limited data available from human studies suggest that the BCG strain used for vaccination is not a significant determinant of the overall efficacy in the prevention of tuberculosis.

BCG Vaccine↗

PubMed1995

Low-dose bacille Calmette-Guérin (BCG) therapy in superficial high-risk bladder cancer: a phase II study with the BCG strain Connaught Canada.

OBJECTIVE: To evaluate low-dose bacille Calmette-Guérin (BCG) therapy, with the Connaught Canada strain, in patients with superficial transitional cell carcinoma (STCC) of the urinary bladder. PATIENTS AND METHODS: Between September 1990 and December 1992 25 patients were entered into a phase II study to evaluate the feasibility, response and toxicity of BCG immunotherapy for patients with high-risk STCC. Therapy consisted of six, weekly instillations of 27 mg (3 x 10(8) colony-forming units) of the BCG strain Connaught Canada. Maintenance therapy was administered monthly for 1 year with the same dosage. RESULTS: Of 25 eligible patients, 84% had complete responses after the initial cycle with low-dose BCG and had stable disease. Four patients had no response, three of whom subsequently underwent radical cystectomy. The mean length of follow-up was 30.8 months (25-36). Toxicity included profound local reactions such as severe dysuria, frequency and gross haematuria. No systemic infections, except fever, were seen; none of the patients needed isoniazid. All reactions were treated symptomatically. CONCLUSIONS: The results of this study suggest that low-dose BCG with the strain Connaught Canada can be successfully used in the treatment of patients with high-risk STCC. Toxicity was not reduced substantially by the lower dosage of BCG used.

Administration, Intravesical↗

PubMed1994

Antigen provoking gamma interferon production in response to Mycobacterium bovis BCG and functional difference in T-cell responses to this antigen between viable and killed BCG-immunized mice.

It has been shown that gamma interferon (IFN-gamma)-producing CD4+ T cells, which are generated only by immunization with viable bacteria, exert a significant role in protective immunity against mycobacteria in mice. In this study, we have tried to determine the antigen recognized by the T cells in search of a possible protective antigen. T cells from viable Mycobacterium bovis BCG-immunized mice were stimulated with several antigens, and IFN-gamma production was measured. Purified protein derivative and viable and killed BCG lysates caused significant IFN-gamma production, and almost the same level of IFN-gamma activity was detected in both groups stimulated with viable and killed BCG lysates. However, heat shock protein (HSP) 65 and HSP 70 were not a major antigen for IFN-gamma production. The antigen provoking IFN-gamma production is localized mainly in the membrane fraction of BCG cells, and the approximate molecular size was 18 kDa. On the other hand, T cells from killed BCG-immunized mice never responded to this antigen for IFN-gamma production, whereas they could mount a delayed-type hypersensitivity response. These results showed that the antigen provoking IFN-gamma production was present in killed as well as viable BCG. In addition to the antigen presentation by antigen-presenting cells, some kinds of differentiation factor (such as monokines) that are produced only by stimulation with viable cells seemed to be necessary for the development of IFN-gamma-producing T cells.

Animals↗